Priming of innate immunity by low grade inflammation is associated with elevated risks of severe systemic inflammatory response syndrome (SIRS) accompanying disseminated endotoxemia, infection and shock. SIRS presents daunting challenges to critical care medicine due to its high mortality risk. Despite its significant health concerns, no effective treatment is currently available. The lack of clear understanding with regard to the underlying molecular mechanisms is the pressing issue. Priming and pre-conditioning of immune environment is believed to be a major risk factor dictating the outcome of septic shock, a process often referred as a second- hit phenomenon. Humans with adverse conditions such as chronic infections, obesity, and aging tend to have subclinical levels of circulating endotoxin, as well as elevated risks for severe septic shock. We demonstrate that subclinical super low levels of endotoxin can effectively prime innate macrophages for a more robust pro- inflammatory response when challenged with a second high dose LPS. Mechanistically, we reported that IRAK- 1 is essential for the pro-inflammatory priming of macrophages by super low dose LPS through removal of the transcriptional suppressor RelB. Pathologically, mice with a prior-hit of super low dose endotoxin have increased mortality when challenged with a second-hit of high dose endotoxin or CLP sepsis. The priming effect is not observed in IRAK-1 deficient mice. Our key objective is to define the molecular mechanisms responsible for the priming of innate immunity. The long term goal is to facilitate the effective prevention and management of acute septic shock. Our key hypothesis is that low-grade endotoxemia increases septic shock risks by priming innate immunity through IRAK-1 mediated modulation of RelB. To test this hypothesis, we plan to perform the following studies. Aim 1 will characterize the molecular mechanisms responsible for the removal of transcriptional suppressor RelB from pro-inflammatory gene promoters by super low dose LPS. Aim 2 will define the unique upstream pathway responsible for the priming of macrophages by super low dose LPS. Aim 3 will examine the in vivo pathological consequences and mechanisms of super low dose priming. Completion of this project will reveal critical mechanisms responsible for innate immunity priming, and contribute to effective prevention and treatment of SIRS accompanying shock and trauma.